The candidate is an academic gastrointestinal surgeon whose career objective is to become an independently funded clinician scientist. After graduating at the top of his class from college and medical school, the candidate trained in surgery at UCLA. He undertook a Research Fellowship during residency that provided preliminary experience in membrane biology and instilled a strong desire to become a clinician scientist and an innovator in the treatment of gallstones. To develop his research career, the candidate needs significantly more time for scientific pursuits as well as the mentorship of an experienced membrane biologist. His career development plan includes both didactic and practical studies of gallbladder ion transport with the supervision of two highly successful and innovative scientists at the University of Pittsburgh. The environment provided by the Laboratory of Epithelial Cell Biology is outstanding and has already trained numerous accomplished clinician scientists. The sponsors have dedicated their laboratory resources, equipment, and time to insure the candidate's success. The research plan focuses on one therapeutically promising aspect of gallstone pathogenesis: increased salt and water absorption by the gallbladder prior to gallstone formation. Increased electrolyte absorption excessively concentrates gallbladder bile and promotes the crystallization of cholesterol. The potential clinical relevance of increased gallbladder salt and water transport is dramatized by data showing that amiloride prevents the formation of gallstones in cholesterol-fed prairie dogs. Contrary to the paradigm for gallbladder transport described in stone-resistant animals, we now demonstrate electrogenic ion transport in human and prairie dog gallbladder. Alterations in electrogenic ion transport precede the formation of gallstones and cause absorption to increase, and the mechanism is unknown. We propose studies with three Specific Aims to test our hypothesis that electrogenic ion transport confers susceptibility to the formation of gallstones; Aim 1: Determine the mechanism for electrogenic ion transport in prairie dog gallbladder. Although prairie dogs are used extensively as a model of human disease, the basic mechanism for gallbladder ion transport in normal prairie dogs has not been established. Aim 2: Characterize alterations in gallbladder ion transport prior to the formation of gallstones. Using cholesterol-fed animals, we will test our hypothesis that alterations in channel-mediated ion transport stimulate electrolyte absorption and promote gallstones. Aim 3: Determine the mechanism for human gallbladder ion transport in health and disease. Given the high incidence of gallstones in patients with abnormal gallbladder ion transport, these studies will test our hypothesis that increased gallbladder electrolyte absorption is also a cause of gallstones in man. These studies are ideal for teaching the Principal Investigator critical new skills required for a successful research career as a clinician scientist in an era of increasingly sophisticated membrane biology.